The neuropeptide somatostatin (SRIF) exerts diverse physiological actions in the CNS. In the neostriatum, it evokes dopamine release and stimulates locomotor activity. At the cellular SRIF inhibits adenylate cyclase activity and modulates K+ and Ca++ conductances to regulate the firing activity of brain neurons. Alterations in central SRIF neurotransmission occur in Schizophrenia and Alzheimer's disease and has been associated with the behavioral abnormalities of these disorders. The goal of this application is to elucidate the cellular mechanisms by which SRIF induces its central effects. We have found that SRIF stimulates two different receptor subtypes to induce its physiological actions. These receptor subtypes can be selectively activated with the newly developed SRIF agonists MK 678 and CGP 23996. The objective of this proposal is to test the hypothesis that the two SRIF receptors mediate different actions of SRIF. This will be accomplished using a multidisciplinary approach to study the properties of SRIF receptors in the neostriatum, a brain region that expresses both receptor subtypes and in which SRIF receptor induces multiple biological responses. Anatomical techniques will be used to determine whether the SRIF receptor subtypes are localized to different cell populations in the neostriatum. In particular, we will determine whether one of the receptor subtypes is localized to a specialized subregion of the striatum, the extrastriosomal matrix. The SRIF receptors will be independently activated in vivo to test whether they mediate distinct SRIF-induced behaviors. For these studies, MK 678 or CGP 23996 will be microinjected into the nucleus accumbens and their effects on locomotor activity or reward systems, as assessed by the conditioned place preference paradigm, will be measured. To investigate whether SRIF receptor subtypes couple to different cellular effector systems to mediate distinct physiological actions of SRIF, we will examine the ability of MK 678 and CGP 23996 to modulate voltage dependent K+ and Ca++ in neostriatal cells in culture using whole cell patch clamp techniques. In these same cells, we will determine whether the SRIF agonists differentially affect adenylate cyclase activity. In addition to the studies directed at neostriatal SRIF receptors, we will also examine the properties of SRIF receptors in other brain regions. SRIF receptors in limbic regions have been proposed to mediate the cognitive effects of SRIF. We will test whether one of the receptor subtypes selectively mediates the effects of SRIF on cognitive functions. For these studies, we will determine whether SRIF agonists can reverse the learning deficits resulting from the depletion of brain SRIF. To accomplish this, subtype selective agonists will be administered intracerebroventricularly to animals pretreated with cysteamine, to deplete central SRIF, and their effects on two different spacial learning tasks will be determined. If our proposed studies show that subtypes of SRIF receptors mediate distinct physiological actions of SRIF, then it may be possible to use MK 678 and CGP 23996 or their analogs to induce selective central actions of SRIF. This could be useful in the treatment of neuropsychiatric disorders with altered SRIF neurotransmission.